Tumor Innervation: From Bystander to Emerging Therapeutic Target for Cancer

Abstract

Innervation is ubiquitous in diseased tissues, including cancer. Increasing evidence suggests that innervation not only plays a direct role in cancer pain, but is also closely related to disease progression, including cancer growth, metastasis, and drug resistance. At the molecular level, tumor-associated nerves can interact with cancer cells and the tumor microenvironment through neurotrophic factors, thereby promoting tumor occurrence and development, and represent a potential intervention for solid tumors with nerve enrichment. By dissecting the transcriptome dynamics of cancer-associated neurons with single cell resolution, numbers of novel therapeutic targets for tumor denervation have been uncovered, including a novel phenomenon-Macrophage to Neuron-like cell Transition (MNT). This review systematically summarizes the latest research findings of tumor denervation, from molecular mechanisms to the innovative denervation strategies, paving the way for novel, safe, and effective cancer treatments in the clinic.

Keywords: denervation therapy; tumor innervation; tumor–nerve crosstalk.

Figure 1

The pathogenic roles and molecular mechanisms of tumor-associated nerves in cancer. Tumor-associated nerves actively secrete neuronal transmitters into the tumor microenvironment, including calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), norepinephrine (NE), and substance P (SP). They can directly activates their respective receptors on the cancer cells (e.g., TrkA (NGF), TrkB (BDNF), β2/β3-adrenergic receptors (NE), NK1R (SP), and the RAMP1/CLR complex (CGRP)) for promoting tumor growth, metastasis, immune evasion, as well as cancer pain formation. Neurotrophic factors (NGF, BDNF, GDNF) also provide trophic support for nerve survival and growth, whereas axon guidance molecules (e.g., semaphorins, ephrins, netrins) regulate directional neural ingrowth within tumors. Red upward arrows: Upregulation of neuronal secretions and their effects. Curved red arrows: Reciprocal support for nerve growth and ingrowth. Straight black arrows: Direction of signaling from neuron secretions to receptors. Black arrows (to right side): Contribution of neuronal sig-naling to growth/metastasis, immune evasion, and cancer pain.

Figure 2

Macrophage to Neuron-like cell Transition (MNT). The tumor-associated macrophages can be further differentiated into functional neuron-like cells in tumor under chronic inflammation via a TGF-β/Smad3 dependent mechanism named MNT, which is primarily induced by tumor cell–secreted TGF-β1. These MNT-derived neurons highly express pain-related genes, including TRPV1, ANO1, POU4F1, and directly contribute to the formation of cancer pain, representing a novel neuro-immune axis in the tumor microenvironment. Straight red arrows: Upregulation of TGF-β signaling. Red upward arrows: Upregulation of gene expression and cancer-associated pain. Black arrows: Direction of cellular transitions and signaling events.